Obstructive sleep apnea is a common disorder linked to the increasing prevalence of obesity in Western society. It is due to recurrent episodes of upper airway obstruction during sleep. Underlying anatomic alterations and/or disturbances in upper airway neuromuscular control are thought to play key roles in the pathogenesis of obstructive sleep apnea, as does obesity, a potent risk factor for this disorder. This proposal investigates the mechanisms linking obesity with sleep apnea, and is based on the concept that differences in regional fat distribution cause upper airway dysfunction during sleep. Regional differences in visceral and subcutaneous fat have been associated with mechanical alterations and distinct profiles of CNS-acting signaling proteins (adipokines) that may affect the neuromechanical control of upper airway patency. Our primary hypothesis is that relative differences in the distribution, signaling and gene expression of adipose tissue modulate upper airway neuromechanical function in severe obesity. This hypothesis is predicated on strong preliminary data implicating regional adiposity in the regulation of upper airway function during sleep. Our data indicate that striking differences in fat distribution, adipokines and gene expression can either protect or compromise upper airway patency during sleep. Discrete physiologic phenotypes reflecting upper airway mechanical loads (passive Pcrit) and compensatory neural responses (deltaVimax and deltaEMGGG) will be assessed to characterize the degree of upper airway dysfunction across the spectrum from health to disease. Novel surgical weight loss strategies will be utilized to elucidate the effects of regional fat distribution, adipokines and gene expression on upper airway neuromechanical control. In cross-sectional (SA#1) and longitudinal human studies (SA#2), we will establish how these factors impact on upper airway function during sleep. In complementary murine studies, unique weight loss interventions will be employed to implicate specific mechanical, humoral and molecular pathways controlling upper airway function (SA#3). This proposal will elucidate the mechanisms and causal pathways linking obesity with upper airway dysfunction during sleep, and will provide novel humoral and molecular predictors of disease susceptibility and treatment responses.